52

Retinoblastoma

At-A-Glance
SUMMARY OF CHANGES

Clinical Classification
●
The definitions of T1–T4 were modified
●
The definitions for M1 were modified

Pathologic Classification
●
Minor modifications were made to the definitions for pT2–pT4
●
Definition of choroidal invasion, focal versus massive
●
The definitions for pM1 were modified

Other
●
A description of proper processing of the enucleated retinoblastoma globe
for pathological examination was added

ANATOMIC STAGE/PROGNOSTIC GROUPS ICD-O-3

TOPOGRAPHY
No stage grouping applies CODES
C69.2 Retina

ICD-O-3 HISTOLOGY
CODE RANGES
9510–9514

ANATOMY

Primary Site. The retina is composed of neurons and glial cells. The
precursors of the neuronal elements give rise to retinoblastoma, whereas
the glial cells give rise to astrocytomas, which are benign and extremely rare
in the retina. The retina is limited internally by a membrane that separates
it from the vitreous cavity. Externally, it is limited by the retinal pigment
epithelium (RPE) and Bruch’s membrane, which separate it from the
choroid and act as natural barriers to extension of retinal tumors into the
choroid. The continuation of the retina with the optic nerve allows direct
extension of retinoblastomas into the optic nerve and then to the subarach-
noid space. Because the retina has no lymphatics, spread of retinal tumors
is either by direct extension into adjacent structures or by distant metastasis 52
through hematogenous routes.

Retinoblastoma 623
Regional Lymph Nodes. Because there are no intraocular lymphatics, this
category of staging applies only to anterior extrascleral extension. The regional
lymph nodes are preauricular (parotid), submandibular, and cervical.

Local Extension. Local extension anteriorly can result in soft tissue

involvement of the face or a mass protruding from between the lids. Poste-
rior extension results in retinoblastoma extending into the orbit, paranasal
sinuses, and/or brain.

Metastatic Sites. Retinoblastoma can metastasize through hematogenous

routes to various sites, most notably the bone marrow, skull, long bones,
and brain.

RULES FOR CLASSIFICATION

Choroidal Invasion. The presence and the extent (focal vs. massive) of
choroidal invasion by tumor should be stated. Differentiation should be
made between true choroidal invasion and artifactual invasion due to seed-
ing of fresh tumor cells during postenucleation retrieval of tumor tissue
and/or gross sectioning.
Artifactual invasion is identified when there are groups of tumor cells
present in the open spaces between intraocular structures, extraocular
tissues, and/or subarachnoid space.
True invasion is defined as one or more solid nests of tumor cells that
fills or replaces the choroid and has pushing borders. Note: Invasion of
the sub-RPE space, where tumor cells are present under the RPE (but not
beyond Bruch’s membrane into the choroid) is not choroidal invasion.
Focal choroidal invasion is defined as a solid nest of tumor that measures
less than 3 mm in maximum diameter (width or thickness).
Massive choroidal invasion is defined as a solid tumor nest 3 mm or
more in maximum diameter (width or thickness).

Clinical Staging. All suspected cases of retinoblastoma should have a neu-

ral imaging scan. If it is possible to obtain only one imaging study, com-
puterized tomography (CT) is recommended because detection of calcium
in the eye on CT confirms the clinical suspicion of retinoblastoma. The
request should include cuts through the pineal region of the brain. Mag-
netic resonance imaging is particularly useful if extension into either the
extraocular space or the optic nerve is suspected or if there is a concern
about the possible presence of a primitive neuroectodermal tumor (PNET)
in the pineal region (trilateral retinoblastoma).
A staging examination under anesthesia should include ocular
ultrasound and retinal drawings of each eye, with each identifiable tumor
measured and numbered. Digital images of the retina may be very helpful.
In bilateral cases, each eye must be classified separately. Tumor size or the
distance from the tumor to the disc or fovea is recorded in millimeters. These
millimeter distances are measured by ultrasound, estimated by comparison
with a normalized optic disc (1.5 mm), or deduced from the fact that the field
of a 28-diopter condensing lens has a retinal diameter of 13 mm.

624 American Joint Committee on Cancer • 2010

Pathologic Staging. If one eye is enucleated, pathologic staging of that eye
provides information supplemental to the clinical staging. First, the patho-
logy should provide histologic verification of the disease. All clinical and
pathologic data from the resected specimen are to be used.

Processing the Enucleated Retinoblastoma Globe. In certain situations

fresh tumor material may be needed from the enucleated globe for research
purposes or genetic testing. In these cases the globe should be moved to
a sterile area in the Operating Room away from the operative field. After
collecting the specimen, the surgeon should change his/her gloves before
reentering the operative field.

Processing With Tumor Sampling. To collect the tumor specimen, the

optic nerve should be removed before opening the globe to prevent the
optic nerve from accidentally becoming contaminated with artifactual
clumps of tumor cells (so-called floaters). The surgeon should first ink
the surgical margin of the optic nerve, then cut the optic nerve stump off
from the sclera with a sharp razor about 2 mm behind the globe. The optic
nerve stump should be placed into a jar of 10% buffered formaldehyde
that will be kept separate from the globe. Then, a sample of tumor should
be obtained by opening a small sclero-choroidal window adjacent to the
tumor near the equator with a 6–8 mm corneal trephine. Once the open-
ing into the vitreous chamber is established, tumor tissue should be gently
removed with forceps and scissors. It is best to leave a hinge on one side of
the scleral flap so that it can be closed with one or two suture(s) following
the removal of tumor sample. This is done in an attempt to maintain the
overall spherical architecture of the specimen during fixation. The globe
should be placed in a second jar of formalin (separate from the optic nerve
stump) and be allowed to fix for at least 24–48 h.

Processing Without Tumor Sampling. If there is no need for fresh tissue

sampling, the enucleated globe should simply be fixed in 10% buffered
formaldehyde for at least 24 and preferably 48 h. When the fixed globe is
examined by the pathologist, if the optic nerve was not previously ampu-
tated in the operative room, that should be performed first as described
previously. The surgical margin of the nerve stump should be embedded
face down in paraffin for sectioning (i.e., thereby obtaining cross-sections
of the nerve, starting at the surgical margin). Then, the eye itself is sec-
tioned. First, a section should be made that extends from pupil through
the optic nerve (the “P-O” section), which contains the center of the optic
nerve with all the optic nerve structures (optic nerve head, lamina crib-
rosa, and postlaminar optic nerve). Preferably this plane should bisect the
largest dimension of the tumor, previously identified by transillumination
and during clinical examination. When possible, the plane should avoid the
scleral opening if one was made for fresh tumor sampling. This section is
critical for evaluation of the optic nerve for tumor invasion. The P-O sec-
tion and minor calottes are then embedded in paraffin. The embedded P-O
calotte is then sectioned every 100–150 µm (each section being about 5 µm
thick), for a total of about 10–20 sections. Additional sections should also 52
be made anterior-posteriorly in a bread loaf fashion through the minor

Retinoblastoma 625
calottes if they contain visible tumor. These segments should be submit-
ted in one cassette per calotte on edge to evaluate the choroid for invasion.
Three levels of this block are usually sufficient for examination. In total,
four cassettes are submitted: the optic nerve stump, the P-O section, and
the two minor calottes (unless one or both of these has no visible tumor).

PROGNOSTIC FEATURES
There are a number of key prognostic factors that are important to col-
lect in retinoblastoma even though they are not required for staging algo-
rithms. These include the presence or absence of an RB gene mutation, a
family history of retinoblastoma, and whether the primary globe-sparing
treatment failed, and the greatest extent of choroid involved by choroidal
tumor invasion.

DEFINITIONS OF TNM

Clinical Classification (cTNM)

Primary Tumor (T)

TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumors no more than 2/3 the volume of the eye with no vitreous
or subretinal seeding
T1a No tumor in either eye is greater than 3 mm in largest dimension
or located closer than 1.5 mm to the optic nerve or fovea
T1b At least one tumor is greater than 3 mm in largest dimension or loca-
ted closer than 1.5 mm to the optic nerve or fovea. No retinal detach-
ment or subretinal fluid beyond 5 mm from the base of the tumor
T1c At least one tumor is greater than 3 mm in largest dimension or
located closer than 1.5 mm to the optic nerve or fovea, with reti-
nal detachment or subretinal fluid beyond 5 mm from the base of
the tumor
T2 Tumors no more than 2/3 the volume of the eye with vitreous or
subretinal seeding. Can have retinal detachment
T2a Focal vitreous and/or subretinal seeding of fine aggregates of tumor
cells is present, but no large clumps or “snowballs” of tumor cells
T2b Massive vitreous and/or subretinal seeding is present, defined as
diffuse clumps or “snowballs” of tumor cells
T3 Severe intraocular disease
T3a Tumor fills more than 2/3 of the eye
T3b One or more complications present, which may include tumor-
associated neovascular or angle closure glaucoma, tumor exten-
sion into the anterior segment, hyphema, vitreous hemorrhage,
or orbital cellulitis
T4 Extraocular disease detected by imaging studies
T4a Invasion of optic nerve
T4b Invasion into the orbit
T4c Intracranial extension not past chiasm
T4d Intracranial extension past chiasm

626 American Joint Committee on Cancer • 2010

Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node involvement
N1 Regional lymph node involvement (preauricular, cervical,
submandibular)
N2 Distant lymph node involvement

Metastasis (M)
M0 No metastasis
M1 Systemic metastasis
M1a Single lesion to sites other than CNS
M1b Multiple lesions to sites other than CNS
M1c Prechiasmatic CNS lesion(s)
M1d Postchiasmatic CNS lesion(s)
M1e Leptomeningeal and/or CSF involvement

Pathologic Classification (pTNM)

Primary Tumor (pT)

pTX Primary tumor cannot be assessed
pT0 No evidence of primary tumor
pT1 Tumor confined to eye with no optic nerve or choroidal
invasion
pT2 Tumor with minimal optic nerve and/or choroidal invasion:
pT2a Tumor superficially invades optic nerve head but does not extend
past lamina cribrosa or tumor exhibits focal choroidal invasion
pT2b Tumor superficially invades optic nerve head but does not extend
past lamina cribrosa and exhibits focal choroidal invasion
pT3 Tumor with significant optic nerve and/or choroidal invasion:
pT3a Tumor invades optic nerve past lamina cribrosa but not to surgical
resection line or tumor exhibits massive choroidal invasion
pT3b Tumor invades optic nerve past lamina cribrosa but not to
surgical resection line and exhibits massive choroidal invasion
pT4 Tumor invades optic nerve to resection line or exhibits extra-
ocular extension elsewhere
pT4a Tumor invades optic nerve to resection line but no extra-ocular
extension identified
pT4b Tumor invades optic nerve to resection line and extra-ocular
extension identified

Regional Lymph Nodes (pN)

pNX Regional lymph nodes cannot be assessed
pN0 No regional lymph node involvement
pN1 Regional lymph node involvement (preauricular, cervical) 52
N2 Distant lymph node involvement

Retinoblastoma 627
Metastasis (pM)
cM0 No metastasis
pM1 Metastasis to sites other than CNS
pM1a Single lesion
pM1b Multiple lesions
pM1c CNS metastasis
pM1d Discrete mass(es) without leptomeningeal and/or CSF
involvement
pM1e Leptomeningeal and/or CSF involvement

ANATOMIC STAGE/PROGNOSTIC GROUPS

No stage grouping applies

PROGNOSTIC FACTORS (SITE-SPECIFIC FACTORS)

(Recommended for Collection)
Required for staging None
Clinically significant Extension evaluated at enucleation
RB gene mutation
Positive family history of retinoblastoma
Primary globe-sparing treatment failure
Greatest linear extent of choroid involved by choroi-
dal tumor invasion

HISTOLOGIC GRADE (G)

Grade is reported in registry systems by the grade value. A two-grade,
three-grade, or four-grade system may be used. If a grading system is not
specified, generally the following system is used:
GX Grade cannot be assessed
G1 Well differentiated
G2 Moderately differentiated
G3 Poorly differentiated
G4 Undifferentiated

HISTOPATHOLOGIC TYPE
This classification applies only to retinoblastoma.

BIBLIOGRAPHY
Chantada G, Doz F, Antoneli CB, Grundy R, Clare Stannard FF, Dunkel IJ, et
al. A proposal for an international retinoblastoma staging system. Pediatr
Blood Cancer. 2006;47:801–5.
Chantada GL, Doz F, Orjuela M, Qaddoumi I, Sitorus RS, Kepak T, Furmanchuk
A, Castellanos M, Sharma T, Chevez-Barrios P, Rodriguez-Galindo C; on

628 American Joint Committee on Cancer • 2010

 behalf of the International Retinoblastoma Staging Working Group. World
disparities in risk definition and management of retinoblastoma: a report
from the International Retinoblastoma Staging Working Group. Pediatr
Blood Cancer. 2008;50:692–4.
Cohen MD, Bugaieski EM, Haliloglu M, Faught P, Siddiqui AR. Visual presentation
of the staging of pediatric solid tumors. Radiographics. 1996;16:523–45.
Dagher R, Helman L. Rhabdomyosarcoma: an overview. Oncologist. 1999;4:34–44.
Ellsworth RM. The practical management of retinoblastoma. Trans Am
Ophthalmol Soc. 1969;67:462–534.
Fleming ID. Staging of pediatric cancers: problems in the development of a
national system. Semin Surg Oncol. 1992;8:94–7.
Warrier RP, Regueira O. Wilms’ tumor. Pediatr Nephrol. 1992;6:358–64.

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Retinoblastoma 629
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